With advancing age, senescent fat cell progenitors, or preadipocytes, accumulate and lead to impaired adipogenesis and increased inflammation. We propose this contributes to age-related fat tissue dysfunction. Senescent preadipocytes acquire a senescence-associated secretory phenotype (SASP), which entails secretion of pro-inflammatory cytokines, chemokines, and ECM-remodeling proteases. We found that lL-6 and TNFa, both of which inhibit adipogenesis, activate Jak/Stat, increase C/EBPB, and further induce senescence and the SASP. Strikingly, by inhibiting Jak, we rescued the age-related decline in preadipocyte differentiation, reduced the SASP in preadipocytes from old animals, and prevented induction of senescence and the SASP in cells from young animals caused by cytokines. Our hypothesis is that inhibiting Jak/Stat will ameliorate the age-related preadipocyte senescent pro-inflammatory secretory phenotype and restore fat tissue function. We propose the following Specific Aims: Aim 1 Dissect mechanisms responsible for preadipocyte senescence and the secretory phenotype. We will focus on IL-6 TNFa, Jaks, and Stats in preadipocytes from animals of different ages. We will determine how cytokines and Jak/Stat components are related to the SASP. We will test if these relations are causal by inhibiting Jaks and varying upstream activators and downstream targets. We will test the role of senescent preadipocytes by selectively eliminating them from populations cultured from INK-ATTAC mice. Aim 2 Determine functional consequences of the preadipocyte SASP. Based on our characterization of the preadipocyte SASP, we will determine how the SASP interferes with adipogenesis, impairs fat cell glucose uptake, and promotes macrophage migration. We will determine how interfering with Jak and mTOR corrects functional deficits at the cellular level. Aim 3 Rescue age-related functional declines by interfering with Jak/Stat-mediated senescence. We will test if Jak inhibitors reduce frailty, senescence, inflammation, and dysfunction in aging animals. To determine if benefits of Jak inhibition occur through effects on senescent cells, we will compare the impact of inhibiting Jak to the other interventions in this PPG and test if inhibiting Jak reduces fat tissue senescent cell abundance and inflammation in subjects enrolled in a Jak inhibitor clinical trial. This research will fill fundamental gaps in understanding how cellular senescence and inflammation are linked in fat tissue and the functional consequences of this. Targeting the fat tissue SASP using Jak inhibitors that are already in clinical use for other indications is a promising path to developing interventions for age-related frailty.